Function of a mutant ryanodine receptor (T4709M) linked to congenital myopathy.
Function of a mutant ryanodine receptor (T4709M) linked to congenital myopathy.
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DOI：
10.1038/s41598-023-41801-2
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发表时间：
2023-09-05
影响因子：
4.6
通讯作者：
中科院分区：
文献类型：
--
作者：
生理肌肉收缩需要肌浆网Ca2+释放通道ryanodine受体1 （RyR1）的完整配体门控机制。一些突变损害门控从而引起肌肉疾病。RyR1突变T4706M与以肌肉无力为特征的肌病有关。尽管T4706M RyR1蛋白的低表达可以部分解释这些症状，但对于这种突变的RyR1通道的功能知之甚少。为了了解这种突变是否以一种可以解释所观察到的症状的方式改变通道功能，我们在单通道水平上检查了从T4709M （TM）突变纯合的小鼠中分离的RyR1通道。配体包括Ca2+、ATP、Mg2+和RyR抑制剂丹曲林。TM通道的全电导与野生型（wt）通道相同，未观察到部分开放（亚导电）状态的种群。然而，发现了两个独特的TM RyRs亚群。一半的TM通道在低（100 nM）和高（50 μM）细胞质[Ca2+]处表现出高打开概率，导致Ca2+不敏感，组成高Po通道。其余的TM通道在细胞质[Ca2+]的生理相关范围内表现出明显较低的活性，与wt相比。TM通道保留了正常的Mg2+阻断，ATP调节和丹曲烯抑制。总之，这些结果表明，TM突变导致原发性和继发性RyR1功能障碍的结合，从而促进疾病的发病机制。
Physiological muscle contraction requires an intact ligand gating mechanism of the ryanodine receptor 1 (RyR1), the Ca2+-release channel of the sarcoplasmic reticulum. Some mutations impair the gating and thus cause muscle disease. The RyR1 mutation T4706M is linked to a myopathy characterized by muscle weakness. Although, low expression of the T4706M RyR1 protein can explain in part the symptoms, little is known about the function RyR1 channels with this mutation. In order to learn whether this mutation alters channel function in a manner that can account for the observed symptoms, we examined RyR1 channels isolated from mice homozygous for the T4709M (TM) mutation at the single channel level. Ligands, including Ca2+, ATP, Mg2+ and the RyR inhibitor dantrolene were tested. The full conductance of the TM channel was the same as that of wild type (wt) channels and a population of partial open (subconductive) states were not observed. However, two unique sub-populations of TM RyRs were identified. One half of the TM channels exhibited high open probability at low (100 nM) and high (50 μM) cytoplasmic [Ca2+], resulting in Ca2+-insensitive, constitutively high Po channels. The rest of the TM channels exhibited significantly lower activity within the physiologically relevant range of cytoplasmic [Ca2+], compared to wt. TM channels retained normal Mg2+ block, modulation by ATP, and inhibition by dantrolene. Together, these results suggest that the TM mutation results in a combination of primary and secondary RyR1 dysfunctions that contribute to disease pathogenesis.
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影响因子：
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作者：
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通讯作者：
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影响因子：
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通讯作者：
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